Z~i[ÌÍl(uÒFDavid Feldman, M.D.j
Vitamin D and the Diseases Causing
David Feldman, M.D.
Professor of Medicine Division of Endocrinology Stanford
University School of Medicine, Stanford CA
@Rickets is mainly
caused by the abnormal metabolism of calcium and/or Vitamin
D resulting in hypocalcemia or hypophosphatemia. The causes
of rickets include; (1) inadequate diet or poor UV exposure,
(2) inability to produce calcitriol (Vitamin D dependent rickets
type I (VDDR-I)), (3) inability to respond to calcitriol (hereditary
Vitamin D resistant rickets (HVDRR or VDDR-II)), (4) phosphaturic
diseases [tumor induced osteomalacia (TIO), X-linked hypophosphatemia
(XLH), autosomaldominant hypophosphatemic rickets (ADHR)].
@VDDR-I is caused by mutations in the gene that codes for
1¿-hydroxylase, the enzyme that produces the active hormone
calcitriol. Defective enzyme results in deficiency of calcitriol
and gives rise to hypocalcemia and hypophosphatemia and causes
rickets. The disease can be treated by the administration
of calcitriol which bypasses the defect.
@HVDRR is caused by mutations in the gene that codes for the
Vitamin D receptor (VDR). Defective VDR causes resistance
to the action of calcitriol. However, long term intravenous
administration of calcium is effective in treating HVDDR by
bypassing the abnormality in absorption of calcium at the
small intestine. Children treated in this way show restoration
of hypocalcemia to normal and resolution of their rickets.
Alopecia is another interesting manifestation of HVDDR. Mutations
causing defective DNA binding or premature stops cause the
alopecia presumably through the inhibition of the interactions
between the VDR, RXR and the vitamin D response element in
target genes. In contrast, several patients with mutations
in the ligand-binding domain of the VDR do not show alopecia.
The findings suggest that the presence of the VDR may prevent
alopecia, even if calcitrol cannot bind the VDR and induce
transactivation of target genes.
@Fibroblast growth factor (FGF)-23 action has been demonstrated
to be cause phosphaturia and hypophosphatemia and is now called
a "phosphatonin". TIO, ADHR and XLH are all caused
by an excess of FGF-23. TIO is due to over-production of FGF-23
by a tumor, ADHR is due to mutations of the FGF-23 gene that
prevent its inactivation, and XLH is due to mutations of PHEX,
which is the enzyme that cleaves FGF-23 to inactivate it.
However, evidence suggests that there may be other phosphatonins
in addition to FGF-23.